Introduction: Brain malformations

Abstract

This issue of the American Journal of Medical Genetics Seminar Series Part C is dedicated to congenital brain malformations with a special focus on the molecular mechanisms underlying this fascinating, and often complex, group of developmental brain disorders. As with most genetic disorders, the past few years have witnessed a dramatic leap in our understanding of the molecular basis of these malformations that include both constitutional and post-zygotic (or mosaic) genetic aberrations. This is best exemplified by the recent identification of mutations within components of the PI3K-AKT-mTOR pathway in hemimegalencephaly and megalencephaly syndromes, and the rapidly increased identification of mutations within the tubulin family in a broad range of cortical and non-cortical brain malformations. These discoveries, particularly of the emerging "tubulinopathies" spectrum, have not only expanded our knowledge of these disorders but challenge our existing, and perhaps overly simplistic, classification of these malformations based on the primary neuronal stage at which the abnormality occurs. It is our hope that this series will facilitate a deeper understanding of these malformations beyond their clinical and neuroimaging features and syndromic associations to their molecular and pathway underpinnings. We believe this knowledge will most certainly be instrumental as we move into the era of delineating genotype-phenotype correlations and, ultimately, pathway-based therapies.

Keywords: brain malformations; genetics; review.